Approximately 300,000 new cases of oral cancer are diagnosed each year, causing over 120,000 deaths worldwide. In addition, because of the location of these cancers, standard surgery and radiation treatments cause acute patient discomfort and disfigurement. We propose to develop a novel approach to prevent and treat oral cancer. Oral squamous cell carcinoma (OSCC) causes about 90% of oral cancers. OSCC cell motility contributes to tumor invasion and metastasis that causes most oral cancer deaths. Extracellular receptors that promote this motility could serve as chemotherapeutic targets. Podoplanin (PDPN) is a unique transmembrane receptor that promotes tumor cell migration, invasion, and metastasis. Basal PDPN expression levels are low in most tissues, but strongly induced in over 70% of oral cancers. Antibodies against PDPN can inhibit tumor progression, but in vivo antibody administration is challenging. PDPN is modified by ?2,3-sialic acid which can be targeted by specific lectins. Lectins are promising anticancer agents that can survive digestive processing to remain active in vivo. Our Preliminary Studies indicate that PDPN can be phosphorylated at specific sites to control cell motility. In addition, we found that Maackia amurensis seed lectin (MASL) targets PDPN with unexpectedly high efficiency to inhibit tumor cell growth and motility at physiologically relevant concentrations. In addition, MASL can complement other chemotherapeutic compounds to synergistically kill tumor cells. We also found that oral MASL survives digestion and enters the circulatory system to inhibit tumor growth and vascularization without causing damage to normal tissues or organs. We hypothesize that agents can target PDPN to interrupt oncogenic signaling cascades, decrease motility, induce caspase independent necrosis, and inhibit tumorigenesis of OSCC cells. We propose 4 Specific Aims to test this hypothesis and target PDPN to combat oral cancer: (1) Elucidate how PDPN phosphorylation affects cell motility; (2) Determine how agents that target PDPN inhibit OSCC cell motility in vitro; (3) Determine how agents that target PDPN inhibit OSCC cell growth in vitro; (4) Investigate how agents that target PDPN affect OSCC tumor progression in vivo. This project will elucidate fundamental aspects of how PDPN affects tumor cell growth and motility, and how agents that target PDPN, exemplified by MASL, work alone or in synergy with other drugs to inhibit tumorigenesis. This work should help develop novel ways to prevent and treat oral cancer, as well as other cancers expressing PDPN including breast, glioma, melanoma, and other skin cancers.